Platinum compounds are among the most active chemotherapeutic agents available for the treatment of a variety of cancers and tumors. The use of some of these compounds, e.g., cisplatin, is restricted by both toxological and resistance considerations. To overcome these issues, efforts were started to discover novel platinum compounds which do not share certain properties of cisplatin. One compound that was identified is satraplatin (JM216), a platinum (Pt) IV complex. Satraplatin (JM216) was selected for clinical development because of several advantageous properties: (a) high cytotoxic activity in vitro against several solid tumor cell lines, including cisplatin-resistant ones; (b) in vivo antitumor activity against a variety of murine- and human-xenograft tumor models; (c) a relatively mild toxicity profile (such as the absence of kidney toxicity and neurotoxicity), and (d) oral availability.
In Phase 2 clinical trials, satraplatin showed activity against several different cancers, including prostate, ovarian, and small cell lung (SCL) cancers. In a Phase II-III clinical trial in Hormone Refractory Prostate Carcinoma (HRPC) patients, the combination of satraplatin plus prednisone was more active than prednisone alone (ASCO meeting, 2003; Sternberg et al., Oncology (2005) 68, 2). Satraplatin is currently undergoing Phase 3 development in a worldwide registration clinical study evaluating satraplatin plus prednisone versus placebo plus prednisone as second-line cytotoxic chemotherapeutic treatment against hormone refractory prostate cancer. Recently it was reported that the study data show that the results for progression-free survival (PFS) are highly statistically significant (p<0.00001) using the protocol-specified log-rank test. Patients who received satraplatin plus prednisone had a 40% reduction in the risk of disease progression (hazard ratio of 0.6; 95% Confidence Interval: 0.5-0.7) compared with patients who received prednisone plus placebo. The improvement seen in progression-free survival by patients treated with satraplatin increased over time. Progression-free survival at the median (50th percentile) demonstrated a 13% improvement in patients who received satraplatin plus prednisone (11 weeks) compared to patients who received prednisone plus placebo (9.7 weeks). Progression-free survival at the 75th percentile showed an 89% improvement for patients in the satraplatin arm (36 weeks) versus patients in the placebo arm (19 weeks). At 6 months, 30% of patients in the satraplatin arm had not progressed, compared to 17% of patients in the control arm. At 12 months, 16% of patients who received satraplatin had not progressed, compared to 7% of patients in the control arm. All of these analyses were conducted on an intent-to-treat basis. The current standard treatment of HRPC is primarily palliative and includes first line chemotherapeutic regimens with agents such as estramustine, mitoxantrone and taxanes, with docetaxel being increasingly used as a first-line chemotherapeutic agent.
Satraplatin is considerably different from other platinum agents, like e.g. cisplatin. Using a panel of ovarian cancer carcinoma cell lines Kelland et al. (Cancer Res (1992), 52, 822) demonstrated that satraplatin is significantly more cytotoxic than cisplatin, and that satraplatin exhibits selective cytotoxic effects against intrinsically cisplatin-resistant cell lines. Loh et al. (Br. J. Cancer (1992) 66, 1109) confirmed these findings. Loh et al. furthermore came to the conclusion that the increased accumulation of satraplatin, which is a result of its enhanced lipophilicity, accounts for the dramatic increase of the potency of satraplatin over cisplatin. Other studies reporting on the activity of satraplatin towards cell lines with acquired or intrinsic resistance to cisplatin are those of Mellish et al. (Br J Cancer (1993) 68, 240), using human cervical squamous cell carcinoma cell lines, and Orr et al. (Br J Cancer (1994) 70, 415), using murine leukaemia cell lines. In the latter report the cell lines used were not just resistant to cisplatin, but also to tetraplatin and carboplatin.
Furthermore, cisplatin was repeatedly shown not to be effective against prostate cancer. Qazi & Khandekar (Am J Clin Oncol (1983) 6, 203) demonstrated in a phase II trial that cisplatin is not effective in patients with metastatic prostatic carcinoma. Hasegawa et al. (Cancer & Chemother (1987) 14, 3279) reported that the range of effective dose was wider for other platinum agents like carboplatin than for cisplatin. Even in combination treatment, cisplatin-comprising regimens demonstrate limited activity, e.g. in combination with mitoxantrone in metastatic prostate cancer (Osborne et al., Eur J Cancer (1992) 28, 477). Therefore, cisplatin is not a substitute for satraplatin as an agent to be used in prostate cancer.
Twentyman et al. (Cancer Res (1992) 52, 5674) investigated the sensitivity of human lung cancer cell lines with acquired or inherent resistance to cisplatin, to a series of novel platinum compounds, including satraplatin. In this study, cisplatin and carboplatin were found to act very similar, whereas satraplatin did not.
In spite of different routes of administration Kelland et al. (Int J Oncol (1993) 2, 1043) demonstrated the surprising finding that the efficacy of orally administered satraplatin is comparable to that of cisplatin and carboplatin administered intravenously, as determined in human ovarian carcinoma xenograft models. These findings were confirmed by Rose et al. (Cancer Chemother Pharmacol (1993) 32, 197), using murine and human tumor models. McKeage et al. (Cancer Res (1994) 54, 4118) investigated the differences of the schedule dependencies associated with these routes of administration.
In another study by Kelland et al. (Cancer Res (1993) 53, 2581) many of the above mentioned differences between satraplatin and cisplatin were confirmed. Furthermore it was found, that the cytotoxicity of satraplatin was dependent on the time of drug exposure. Again, it was confirmed that satraplatin does not exhibit cross resistance to cisplatin, whereas other platinum agents, e.g. tetraplatin, do. Without being bound to any particular theory, satraplatin circumvents transport-determined acquired resistance to cisplatin.
Mellish et al. (Cancer Res (1994) 54, 6194) investigated the mechanisms of acquired resistance to satraplatin in two human ovarian carcinoma cell lines. They found that, in contrast to cisplatin, acquired resistance to satraplatin is not mediated through reduced drug accumulation, but by increased intracellular GSH levels or increased DNA repair.
Sharp et al. (Clin Cancer Res (1995) 1, 981) compared the transport of cisplatin and satraplatin in human ovarian carcinoma cell lines. Cisplatin transport in the parental cell lines occurs via passive diffusion and active/facilitated transport, whereas in a cisplatin-resistant cell lines cisplatin enters cells by passive diffusion only. Without being bound to any particular theory, satraplatin circumvents cisplatin resistance by increasing the drug uptake. The mechanism of satraplatin transport across cell membranes is through passive diffusion, predominantly as a result of its enhanced lipophilicity.
Fink et al. (Cancer Res (1996) 56, 4881) investigated the effect of the loss of DNA mismatch repair activity on the sensitivity to cisplatin, satraplatin and other platinum agents. In contrast to cisplatin and carboplatin, which form the same type of adducts in DNA, there was no difference in sensitivity between mismatch repair-proficient and mismatch repair-deficient cell lines for satraplatin.
Perego et al. (Mol Pharmacol (1998) 54, 213) investigated the sensitivity of strains of Schizosaccharomyces pombe to cisplatin, satraplatin and other platinum compounds. The panel of the 23 yeast strains tested comprised many mutants in genes that affect the response to radiation. Whereas the mutants fell into three groups with respect to their sensitivity to cisplatin (minimal change in sensitivity, hypersensitivity, and marked hypersensitivity), none of the mutants demonstrated an appreciable change in sensitivity to satraplatin.
Leyland-Jones et al. (Amer J. Pathol (1999), 155, 77) investigated genomic imbalances associated with acquired resistance to platinum analogues. Using three ovarian carcinoma cell lines they identified differences between the three platinum compounds cisplatin, satraplatin and AMD473 (picoplatin).
Amorino et al. (Int J Radiation Oncol Biol Phys (1999), 44, 399) investigated radiopotentiation by satraplatin and the role of repair inhibition. They found that satraplatin can potentiate the effects of radiation in human lung cancer cells, and that the mechanism of this effect is probably inhibition of DNA repair by satraplatin. Differences to other platinum drugs like cisplatin and carboplatin are indicated.
Vaisman et al. (Biochemistry (1999), 38, 11026) reported on the effects of DNA polymerases and high mobility group protein 1 on the carrier ligand specificity for translesion synthesis past platinum-DNA adducts, with respect to different platinum compounds.
Screnci et al. (Br J Cancer (2000) 82, 966) investigated the relationship between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum compounds. According to Screnci et al. the hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system, but not with neurotoxicity.
Wei et al. (J Biol Chem (2001) 276, 38774) reported on the effect of ligands on the specific recognition of intrastrand platinum-DNA cross-links by high mobility group box and TATA-binding proteins, with respect to different platinum compounds.
Fokkema et al. (Biochem Pharmacol (2002) 63, 1989) analysed in detail the satraplatin-, JM118-, and cisplatin-induced cytotoxicities in relation to various parameters like platinum-DNA adduct formation, glutathione levels and p53 status in human tumor cell lines with different sensitivities to cisplatin. It was confirmed that satraplatin and JM118 can partially circumvent intrinsic and acquired resistance to cisplatin. At equimolar basis, satraplatin induced lower levels of platinum-DNA adducts in the cell lines tested compared to cisplatin.
Taken together, fundamental differences exist between satraplatin and other platinum agents, such as cisplatin. These differences are the basis, lead to or play a role in many of the different characteristics of satraplatin, including different pharmacokinetic properties, different efficacy, a different toxicology profile, different ADME properties and different mechanisms that lead to drug resistance, only to name a few.
Receptors of the EGFR family are known targets for cancer. We show, as outlined herein, that inhibitors of receptors of the EGFR family act synergistically with certain platinum-based compounds. This synergistic effect is observed with different receptors of the EGFR family, and the synergistic effect is also not limited by the nature of the compound inhibiting the EGFR receptor. We show that antibodies, as well as small molecules, act synergistically with certain platinum-based compounds on cancer cells and tumor cells.
Pyrimidine analogues inhibit the biosynthesis of pyrimidine nucleotides and/or mimic certain metabolites of this pathway. We demonstrate that such compounds act synergistically with certain platinum-based compounds. It is asserted that this synergism is also observed between prodrugs of pyrimidine analogues or compounds that are metabolised to pyrimidine analogues in the human body.
Synergism between inhibitors of receptors of the EGFR family or chemotherapeutically active pyrimidine analogues with platinum-based chemotherapeutic agents have been demonstrated to some extent in the past. Nagourney et al (Oncology (2001) 15, 28) reported synergism between cisplatin and herceptin in breast cancer. Synergism between inhibitors of receptors of the EGFR family and cisplatin was also reported by Gieseg et al. (Anti-cancer drugs (2001) 12, 683). Mosconi et al (Eur J Cancer (1997) reported synergistic effects between gemcitabin and cisplatin.
However, as evidenced above and shown herein there are fundamental differences between the platinum-compounds of the present invention, such as satraplatin and JM-118, and other platinum compound, such as cisplatin, carboplatin and oxaliplatin. No synergistic effects have so far been reported between the platinum-compounds of the present invention and inhibitors of receptors of the EGFR family or chemotherapeutically active pyrimidine analogues.